Hydrophilic therapeutic agents present difficult problems in formulation. While these therapeutic agents are readily soluble in water, and are easily dissolved in the gastrointestinal environment, simple dissolution is not sufficient to provide efficient bioabsorption of the therapeutic agent. Barriers to absorption are presented by the mucous layer, the intestinal epithelial cell membrane, and the junctional structure such as tight junctions between the epithelial cells. Due to the presence of the negatively charged mucosal layer, significant electrostatic binding or repulsion of charged molecules can be encountered. The epithelial cell membranes are composed of phospholipid bilayers in which proteins are embedded via the hydrophobic segments. These bilayers at the apical and/or basolateral cell surface represent very strong barriers for transport of hydrophilic substances, including peptides and proteins. Frequently, hydrophilic therapeutic agents are also subject to enzymatic attack and are degraded before they can be presented to the absorption site.
Some hydrophilic drugs such as acyclovir, foscarnet, tiludronate, pamidronate, alendronate, acarbose, cromolyn sodium, aminoglycoside and cephalosporin antibiotics are poorly absorbed from the gastro-intestinal tract, due to their low octanol-water partition coefficient, charge, and/or size.
Large water-soluble polymers, such as peptides, proteins, genetic material, vaccines and oligonucleotides, are not well absorbed from the intestine, primarily due to their low membrane permeability and enzymatic inactivation. The mammalian body possesses several efficient mechanisms to restrict the entry of macromolecules. These mechanisms include the presence of significant levels of enzymatic activity at various locations prior to entry into systemic circulation.
Thus, numerous barriers to absorption of hydrophilic therapeutic agents are present, and these barriers inhibit the effective absorption both of small hydrophilic therapeutic agents, such as conventional non-peptidic drugs, and of macromolecular hydrophilic therapeutic agents, such as proteins, peptides, vaccines and the like.
Much effort has been expended to develop methods of overcoming these absorption barriers. For example, the enzymatic barrier can be attacked by administering enzyme inhibitors to prevent or at least lessen the extent of presystemic degradation in the gastrointestinal tract (see, e.g., Bernkop-Schnurch, "The use of inhibitory agents to overcome the enzymatic barrier to perorally administered therapeutic peptides and proteins", Journal of Controlled Release, 52, 1-16 (1998)). Other efforts have focused on, for example, the use of absorption promoters to enhance epithelial permeability (e.g., LeCluyse and Sutton, "In vitro models for selection of development candidates. Permeability studies to define mechanisms of absorption enhancement", Advanced Drug Delivery Reviews, 23, 163-183 (1997)). However, the effectiveness of absorption enhancers such as permeability enhancers or enzyme inhibitors depends upon the ability of a pharmaceutical carrier to effectively present the absorption enhancers and the hydrophilic therapeutic agent to the absorption site, and prior efforts have not provided carriers which can do so efficiently. Moreover, maintaining effective carrier concentrations at the epithelium is not easily controlled in vivo. Too little carrier, or carrier concentrations only briefly maintained, may be ineffective. Too much carrier, or carrier concentrations maintained for too long, may result in compromised safety.
Frequently, carrier compositions for hydrophilic therapeutic agents include or are based on triglycerides. For example, U.S. Pat. Nos. 5,444,041, 5,646,109 and 5,633,226 to Owen et al. are directed to water-in-oil ("w/o") microemulsions for delivering water-soluble biological actives, such as proteins or peptides. The water-in-oil microemulsions convert into oil-in-water ("o/w") emulsions upon ingestion. The active agent is initially stored in the internal water phase of the w/o microemulsion, and is released when the composition converts to an o/w emulsion upon mixing with bodily fluids. Other oil-based or oil-containing formulations are taught in, for example, U.S. Pat. No. 5,120,710 to Liedtke, U.S. Pat. No. 5,656,289 to Cho et al. These triglyceride-containing formulations, however, suffer form several disdavantages.
U.S. Pat. No. 5,206,219 to Desai, for example, teaches compositions having a particle size of 5 to 50 microns. Typically, emulsions formed from triglyceride-containing compositions contain colloidal oil particles which are relatively large, ranging from several hundred nanometers to several microns in diameter, in a broad particle size distribution. Since the particle sizes are on the order of or greater than the wavelength range of visible light, such emulsions, when prepared in an emulsion dosage form, are visibly "cloudy" or "milky" to the naked eye. Emulsions are thermodynamically unstable, and colloidal emulsion particles will spontaneously agglomerate, eventually leading to complete phase separation. The tendency to agglomerate and phase separate presents problems of storage and handling, and increases the likelihood that pharmaceutical emulsions initially properly prepared will be in a less optimal, less effective, and poorly-characterized state upon ultimate administration to a patient. Uncharacterized degradation is particularly disadvantageous, since increased particle size slows the rate of transport of the colloidal particle and digestion of the oil component, and hence the rate and extent of absorption of the therapeutic agent. These problems lead to poorly-characterized and potentially harmful changes in the effective dosage received by the patient, and/or the rate of drug uptake. Moreover, changes in colloidal emulsion particle size are also believed to render absorption more sensitive to and dependent upon conditions in the gastrointestinal tract, such as pH, enzyme activity, bile components, and stomach contents. Such uncertainty in the rate and extent of ultimate absorption of the therapeutic agent severely compromises the medical professional's ability to safely administer therapeutically effective dosages. In addition, when such compositions are administered parenterally, the presence of large particles can block blood capillaries, further compromising patient safety.
U.S. Pat. No. 5,626,869 to Nyqvist et al. discloses compositions that would likely produce discrete lipid particles of relatively large size in vivo. Such particles suffer from the disadvantages of large size and low diffusivity, and are unable to effectively present any absorption enhancing components to the site of absorption.
A further disadvantage of conventional triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis. Ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa. The triglyceride carrier is emulsified by bile salts and hydrolyzed, primarily by pancreatic lipase. The rate and extent of lipolysis, however, are dependent upon several factors that are difficult to adequately control. For example, the amount and rate of bile salt secretion affect the lipolysis of the triglycerides, and the bile salt secretion can vary with stomach contents, with metabolic abnormalities, and with functional changes of the liver, bile ducts, gall bladder and intestine. Lipase availability in patients with decreased pancreatic secretory function, such as cystic fibrosis or chronic pancreatitis, may be undesirably low, resulting in a slow and incomplete triglyceride lipolysis. The activity of lipase is pH dependent, with deactivation occurring at about pH 3, so that the lipolysis rate will vary with stomach contents, and may be insufficient in patients with gastric acid hyper-secretion. Moreover, certain surfactants commonly used in the preparation of pharmaceutical emulsions, such as polyethoxylated castor oils, may themselves act as inhibitors of lipolysis.
Other carrier formulations avoid the use of triglycerides, but still suffer disadvantages. For example, U.S. Pat. No. 5,653,987 to Modi et al. is directed to pharmaceutical formulations for oral or nasal delivery of proteinaceous pharmaceutical agents using small amounts of particular surfactants and a protease inhibitor in an aqueous medium as absorption enhancers. However, in the gastrointestinal tract, where the volume of liquids is large and motility is great, polar drugs and the protease inhibitor are diluted even further upon administration, thus negating any potential benefits, since the composition is unable to deliver meaningful amounts of the absorption enhancers and pharmaceutical agents to the absorption site.
Thus, there is a need for pharmaceutical compositions that overcome the limitations of conventional formulations, to provide effective delivery of absorption enhancers and enhanced absorption of hydrophilic therapeutic agents.